Cavernous angioma
Encyclopedia
Cavernous angioma, also known as cerebral cavernous malformation (CCM), cavernous haemangioma, and cavernoma, is a vascular disorder that alternately has been classified as neoplastic or hamartomatous. It is characterized by grossly dilated blood vessels with a single layer of endothelium
and an absence of neuronal tissue within the lesions. These thinly walled vessels resemble sinusoidal cavities filled with stagnant blood. Blood vessels in patients with CCM can range from a few millimeters to several centimeters in diameter. Most lesions occur in the brain, but any organ may be involved.
. It may appear either sporadically or exhibit autosomal dominant inheritance.
origin include recurrent headache
s, focal neurological deficits, hemorrhagic stroke
, and seizures, but CCM can also be asymptomatic
. The nature and severity of the symptoms depend on the lesion's location.
Diagnosis is generally made by magnetic resonance imaging
(MRI), particularly using a specific imaging technique known as a gradient-echo sequence MRI, which can unmask small or punctate lesions that may otherwise remain undetected. These lesions are also more conspicuous on FLAIR imaging compared to standard T2 weighing. FLAIR imaging is different from Gradient sequences, rather, it is similar to T2 weighing but suppresses free-flowing fluid signal. Sometimes quiescent CCMs can be revealed as incidental findings during MRI exams ordered for other reasons. Many cavernous hemangiomas are detected "accidentally" during MRIs searching for other pathologies. These "incedentalomas" are generally asymptomatic. In the case of hemorrhage, however, a CT scan is more efficient at showing new blood than an MRI, and when brain hemorrhage is suspected, a CT scan may be ordered first, followed by an MRI to confirm the type of lesion that has bled.
Sometimes the lesion appearance imaged by MRI remains inconclusive. Consequently neurosurgeons will order a cerebral angiogram
or magnetic resonance angiogram
(MRA). Since CCMs are low flow lesions (they are hooked into the venous side of the circulatory system), they will be angiographically occult (invisible). If a lesion is discernible via angiogram in the same location as in the MRI, then an arteriovenous malformation
(AVM) becomes the primary concern.
, a radial orientation of small vessels that resemble the hair of Medusa
from Greek mythology
. These lesions are thought to represent developmental anomalies of normal venous drainage. These lesions should not be removed, as venous infarcts have been reported. When found in association with a CCM that needs resection, great care should be taken not to disrupt the angioma.
(krev interaction trapped 1) and has been found to bind to ICAP1alpha (integrin cytoplasmic domain associated protein alpha), a beta1 integrin
associated protein. The gene for CCM2
encodes a novel protein named malcavernin that contains a phosphotyrosine (PTB) binding domain. The exact biological function of CCM2 is not clear. Recently, it has been shown that CCM1 and CCM2 proteins as well as ICAP1alpha form a macromolecular complex in the cell. In addition, it appears that CCM2 protein may function as a scaffolding protein for MAP kinases that are essential in p38
activation responding to osmotic stress including MEKK3 and MKK3. It also binds to Rac
and actin
. Therefore, CCM2 protein is also called OSM (osmosensing scaffold for MEKK3). The CCM3 gene is the most recently identified CCM gene . CCM3 is known as PDCD10
(programmed cell death 10), which was initially identified as a gene that is up-regulated during the induction of apoptosis
(cell death) in TF-1, a human myeloid
cell line. The precise role of the PDCD10 protein in the CCM pathway is not clear. It is recently shown that PDCD10 forms a complex with CCM1 protein (KRIT1) and CCM2 protein (OSM). PDCD10 interacts directly with OSM independent of KRIT1-OSM interaction. Research is ongoing to determine the function and properties of all three CCM gene products as well as the reaction pathways in which they are involved. A fourth gene, CCM4, has been identified but not yet fully elucidated
Mutations in these genes account for 70 to 80 percent of all cases of cerebral cavernous malformations. The remaining 20 to 30 percent of cases may be due to other, still unidentified, genes.
Malformation, Familial]
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
and an absence of neuronal tissue within the lesions. These thinly walled vessels resemble sinusoidal cavities filled with stagnant blood. Blood vessels in patients with CCM can range from a few millimeters to several centimeters in diameter. Most lesions occur in the brain, but any organ may be involved.
Incidence
The incidence in the general population is roughly 0.5%, and clinical symptoms typically appear between 20 to 30 years of age. Once thought to be strictly congenital, these vascular lesions have been found to occur de novoDe novo
In general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
. It may appear either sporadically or exhibit autosomal dominant inheritance.
Symptoms and diagnosis
Clinical symptoms of CNSCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
origin include recurrent headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, focal neurological deficits, hemorrhagic stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and seizures, but CCM can also be asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
. The nature and severity of the symptoms depend on the lesion's location.
Diagnosis is generally made by magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI), particularly using a specific imaging technique known as a gradient-echo sequence MRI, which can unmask small or punctate lesions that may otherwise remain undetected. These lesions are also more conspicuous on FLAIR imaging compared to standard T2 weighing. FLAIR imaging is different from Gradient sequences, rather, it is similar to T2 weighing but suppresses free-flowing fluid signal. Sometimes quiescent CCMs can be revealed as incidental findings during MRI exams ordered for other reasons. Many cavernous hemangiomas are detected "accidentally" during MRIs searching for other pathologies. These "incedentalomas" are generally asymptomatic. In the case of hemorrhage, however, a CT scan is more efficient at showing new blood than an MRI, and when brain hemorrhage is suspected, a CT scan may be ordered first, followed by an MRI to confirm the type of lesion that has bled.
Sometimes the lesion appearance imaged by MRI remains inconclusive. Consequently neurosurgeons will order a cerebral angiogram
Angiogram
Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins and the heart chambers...
or magnetic resonance angiogram
Angiogram
Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins and the heart chambers...
(MRA). Since CCMs are low flow lesions (they are hooked into the venous side of the circulatory system), they will be angiographically occult (invisible). If a lesion is discernible via angiogram in the same location as in the MRI, then an arteriovenous malformation
Arteriovenous malformation
Arteriovenous malformation or AVM is an abnormal connection between veins and arteries, usually congenital. This pathology is widely known because of its occurrence in the central nervous system, but can appear in any location. An arteriovenous malformation is a vascular anomaly. It is a...
(AVM) becomes the primary concern.
CCMs & venous angiomas
In up to 30% there is a coincidence of CCM with a venous angioma, also known as a developmental venous anomaly (DVA). These lesions appear either as enhancing linear blood vessels or caput medusaeCaput medusae
Caput medusae is the appearance of distended and engorged paraumbilical veins, which are seen radiating from the umbilicus across the abdomen to join systemic veins...
, a radial orientation of small vessels that resemble the hair of Medusa
Medusa
In Greek mythology Medusa , " guardian, protectress") was a Gorgon, a chthonic monster, and a daughter of Phorcys and Ceto. The author Hyginus, interposes a generation and gives Medusa another chthonic pair as parents. Gazing directly upon her would turn onlookers to stone...
from Greek mythology
Greek mythology
Greek mythology is the body of myths and legends belonging to the ancient Greeks, concerning their gods and heroes, the nature of the world, and the origins and significance of their own cult and ritual practices. They were a part of religion in ancient Greece...
. These lesions are thought to represent developmental anomalies of normal venous drainage. These lesions should not be removed, as venous infarcts have been reported. When found in association with a CCM that needs resection, great care should be taken not to disrupt the angioma.
Familial forms
Familial forms of CCM occur at four known genetic loci. The gene for CCM1 encodes KRIT1KRIT1
Krev interaction trapped protein 1 is a protein that in humans is encoded by the KRIT1 gene.It can be associated with Cavernous venous malformation.-Further reading:...
(krev interaction trapped 1) and has been found to bind to ICAP1alpha (integrin cytoplasmic domain associated protein alpha), a beta1 integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
associated protein. The gene for CCM2
CCM2
Malcavernin is a protein that in humans is encoded by the CCM2 gene.-Further reading:...
encodes a novel protein named malcavernin that contains a phosphotyrosine (PTB) binding domain. The exact biological function of CCM2 is not clear. Recently, it has been shown that CCM1 and CCM2 proteins as well as ICAP1alpha form a macromolecular complex in the cell. In addition, it appears that CCM2 protein may function as a scaffolding protein for MAP kinases that are essential in p38
P38
P38 or P-38 may refer to:* Lockheed P-38 Lightning, a World War II American fighter aircraft built by Lockheed* p38 mitogen-activated protein kinases, a class of mitogen-activated protein kinases, two British Royal Navy ships...
activation responding to osmotic stress including MEKK3 and MKK3. It also binds to Rac
RAC
-Companies:* Rent-A-Center, an American public furniture and electronics rent to own company* Royal Automobile Club, a private club in Pall Mall, London* RAC plc, a breakdown company in the United Kingdom...
and actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
. Therefore, CCM2 protein is also called OSM (osmosensing scaffold for MEKK3). The CCM3 gene is the most recently identified CCM gene . CCM3 is known as PDCD10
PDCD10
Programmed cell death protein 10 is a protein that in humans is encoded by the PDCD10 gene.-Interactions:PDCD10 has been shown to interact with RP6-213H19.1, STK25, STRN, STRN3, MOBKL3, CTTNBP2NL, STK24 and FAM40A.-Further reading:...
(programmed cell death 10), which was initially identified as a gene that is up-regulated during the induction of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(cell death) in TF-1, a human myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
cell line. The precise role of the PDCD10 protein in the CCM pathway is not clear. It is recently shown that PDCD10 forms a complex with CCM1 protein (KRIT1) and CCM2 protein (OSM). PDCD10 interacts directly with OSM independent of KRIT1-OSM interaction. Research is ongoing to determine the function and properties of all three CCM gene products as well as the reaction pathways in which they are involved. A fourth gene, CCM4, has been identified but not yet fully elucidated
Mutations in these genes account for 70 to 80 percent of all cases of cerebral cavernous malformations. The remaining 20 to 30 percent of cases may be due to other, still unidentified, genes.
External links
- Angioma Alliance, provides information and support for those affected
- Cavernoma Alliance UK - a charity created for and by people affected by cavernoma.
- International Cavernous Angioma Patient Registry
- Angioma Alliance Canada, provides information and support for those affected in Canada.
Malformation, Familial]
- http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ccm GeneReviews/NCBI/NIH/UW entry on Cerebral Cavernous
- Atlas of Pathology
- Brain Blood Vessel Disorder Help Site
- Incidental Findings with Brain MRI
- Imaging MR and CT of Cavernous Malformations